POS0097 IDENTIFICATION OF NEW CANDIDATE DRUGS FOR PRIMARY SJÖGREN’S SYNDROME USING A DRUG REPURPOSING TRANSCRIPTOMIC APPROACH
Authors: R. Felten, T. Ye, C. Schleiss, B. Schwikowski, J. Sibilia, F. Monneaux, H. Dumortier, R. Jonsson, C. Lessard, W.F. Ng, T. Takeuchi, X. Mariette, J.E. Gottenberg
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> No immunomodulatory drug has ever demonstrated its efficacy in primary Sjögren's Syndrome (pSS). Drug repurposing, or drug repositioning, refers to the use in another disease of an existing drug, originally approved or evaluated in a different disease. <h3>Objectives</h3> The objective of our study was to repurpose existing therapeutic drugs in pSS using a transcriptomic approach. <h3>Methods</h3> We generated pSS transcriptomic signatures from peripheral blood samples of patients with pSS compared to healthy controls in two cohorts (ASSESS and a Norwegian cohort) and data mined available pSS transcriptomic signatures in public databases. We compared each disease signature to transcriptomic signatures, obtained from the biological action of 2837 drugs, 2160 knock-in and 3799 knock-down genes, available in the Connectivity Map database. A median similarity score with regard to disease signatures was computed for each candidate drug/gene. Drugs and genes were selected if p&lt;0.05 and similarity score &gt;│80│. If this score is sufficiently high and statistically significant (&gt;80, p&lt;0.05), the tested drug or gene, mimics the signature of the disease. Conversely, if this score is sufficiently low and statistically significant (&lt;-80, p&lt;0.05), the tested drug or gene inverts the signature of the disease and might represent a potential treatment or therapeutic target of interest (Figure 1). <h3>Results</h3> 1091 peripheral blood transcriptomes were analyzed from 6 independent studies (906 patients with pSS and 185 healthy controls). Our analysis identified 11 transcriptomic drug signatures significantly associated with pSS signature. We identified 72 transcriptomic knock-in (11) or knock-down (61) gene signatures significantly associated with that of pSS, including 21 with a negative similarity score (Table 1). Type I and II interferons were highly ranked (similarity score &gt;99), and their overexpression mimicked the disease signature. CD40 appeared also as a very relevant target (similarity score = 98.8). Three drugs had a significant negative similarity score: ampicillin (-88.69, p=0.0019), amylocaine (-88.28, p=0.0026), and droxinostat (-85.42, p=0.0027). Droxinostat is a HDAC inhibitor. HDAC activity has been shown to be an essential element of the coactivation system for IFN-induced gene regulation and the IFN-induced innate immune response. <h3>Conclusion</h3> This first drug repositioning transcriptomic approach in Sjögren's syndrome confirms the interest of targeting interferons and identifies histone deacetylases as potential therapeutic targets. <h3>Acknowledgements</h3> Investigators of the ASSESS cohort: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror Centre de Ressources Biologiques de l'Hôpital Bichat: Sarah Tubiana Johan G. Brun for contributing to the Norwegian cohort. <h3>Funding Sources</h3> This work was supported by the Innovative Medicines Initiative 2 Joint Undertaking (IMI 2 JU) (NECESSITY grant 806975). The Joint Undertaking received support from the European Union's Horizon 2020 Research and Innovation Program and from the European Federation of Pharmaceutical Industries and Associations. This work was also supported by R01 AR065953 Beth the NIH, United States. The contents are the sole responsibility of the authors and do not necessarily the official views of the NIH. JEG received an unrestricted grant from Bristol-Myer-Squibbs to do the transcriptomic analysis of the ASSESS and Norwegian cohorts. JEG received a grant from Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs). The ASSESS cohort is promoted by the French Society of Rheumatology and received two research grants from the French Society of Rheumatology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. <h3>Disclosure of Interests</h3> Renaud FELTEN: None declared, Tao Ye: None declared, Cédric Schleiss: None declared, Benno Schwikowski: None declared, Jean Sibilia: None declared, Fanny Monneaux: None declared, Hélène Dumortier: None declared, Roland Jonsson: None declared, Christopher Lessard: None declared, Wan Fai Ng: None declared, Tsutomu Takeuchi: None declared, Xavier Mariette: None declared, Jacques-Eric Gottenberg Grant/research support from: JEG received an unrestricted grant from Bristol-Myer-Squibbs to do the transcriptomic analysis of the ASSESS and Norwegian cohorts.